PROJECT SUMMARY As a research assistant professor in the laboratory of Dr. John Crispino, I lead a major effort to develop novel therapies for patients with blood cancers, I assist other lab members in their translational initiatives, and I collaborate with external colleagues to enhance their cancer research. The main area of my research involves the investigation of the pathogenesis of acute megakaryocytic leukemia (AMKL), and the role of megakaryocytes in the development of other blood cancers, such as primary myelofibrosis (PMF), which is a subtype of the myeloproliferative neoplasms (MPNs). During normal development, megakaryocytes progress through repeated rounds of the cell cycle without cell division to become polyploid. I hypothesized that small molecules that could force malignant megakaryocytes to become polyploid and differentiate would act as anti- tumor agents. Indeed, I discovered that megakaryocytic polyploidy inducing molecules such as dimethylfasudil and MLN8237 (Alisertib), which inhibit Aurora A kinase, have potent anti-AMKL activity in vitro and in vivo. Moreover, these compounds showed strong anti-tumor activity in patient samples and mouse models of PMF. These findings lead to the opening of a Phase 1 clinical trial of Alisertib in patients with AMKL or PMF. From this study I accumulated an enormous amount of experience in drug development from the design of high throughput small molecule and RNAi screens to preclinical studies with animal models. Over the next five years, I will leverage my experience to further my own research as well as to aid lab colleagues in their studies to find new therapies for hematologic malignancies. My work can be divided into four focus areas: A) development of therapies for megakaryocytic malignancies; B) validation of PAK1 as a target in the MPNs; C) development of DYRK1A inhibitors for AMKL and B-ALL; D) investigation of novel therapies to target cohesin mutations in AMKL and AML. I look forward to continuing to be an instrumental leader in Dr. Crispino's lab, to collaborating with other NCI-funded investigators, and to bringing more novel therapeutics to patients.